N o n f u n c t i o n a l P a n c re a t i c

N e u ro e n d o c r i n e Tu m o r s
Jennifer H. Kuo,

MD

, James A. Lee,

MD

b,

*, John A. Chabot,

MD

KEYWORDS
 Pancreas  Neuroendocrine  Nonfunctional  Neuroendocrine liver metastases
 PanNET
KEY POINTS
 Pancreatic neuroendocrine tumors are rare, heterogeneous tumors that compose 3% of
all pancreatic neoplasms and 7% of all neuroendocrine tumors.
 The incidence of pancreatic neuroendocrine tumors has been increasing over the past
20 years because of the increased diagnosis of pancreatic incidentalomas.
 Ninety percent of pancreatic neuroendocrine tumors are nonfunctional tumors that are
often malignant and present with symptoms of mass effect or metastatic disease.
 Formal surgical resection is the treatment of choice for most locoregional disease; however, surgical decision making must include many variables.
 Hepatic metastasis is common, and resection is recommended in the absence of extrahepatic disease.
 Interventional liver-directed therapies and targeted systemic therapies offer promising alternatives for patients with advanced disease, improving morbidity and increasing
progression-free survival.

INTRODUCTION

Neuroendocrine tumors (NETs) are a group of rare, diverse neoplasms, which can be
found throughout the body. They are most commonly located in the gastrointestinal
tract and lung but are also found in the pancreas.1 Historically known as islet cell tumors, they are now classified as pancreatic NETs (PanNETs) by the World Health Organization (WHO). When compared with adenocarcinomas, PanNETs account for a
relatively small percentage of pancreatic neoplasms,2,3 but their incidence has been
increasing over the past 20 years. Based on the Surveillance, Epidemiology, and
End Results (SEER) database, the incidence of NETs in the United States increased

a
Division of GI/Endocrine Surgery, Columbia University, 161 Fort Washington Avenue, 8th Floor,
New York, NY 10032, USA; b COACH Education, Endocrine Surgery, Adrenal Center, New York
Thyroid/Parathyroid Center, Simulation Center, Columbia University, 161 Fort Washington
Avenue, 8th Floor, New York, NY 10032, USA
* Corresponding author.
E-mail address: jal74@columbia.edu

Surg Clin N Am 94 (2014) 689708

http://dx.doi.org/10.1016/j.suc.2014.02.010
surgical.theclinics.com
0039-6109/14/$ see front matter 2014 Elsevier Inc. All rights reserved.

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nearly 5-fold over the past 3 decades and was 5.25 per 100,000 in 2004.4 PanNETs
account for 7% of all NETs5 and have an incidence of 0.43 per 100,000 people in
2007,5 a greater than 2-fold increase in the incidence of PanNETs since the 1980s.
The increased frequency of abdominal imaging, specifically computed tomography
(CT) and ultrasound, has increased the incidence of abnormal pancreatic findings
detected in asymptomatic patients. Of these patients, 17% will ultimately undergo
pancreatectomy.6 This increase in pancreatic incidentalomas may reflect a historical
underestimation of the prevalence of this disease; autopsy studies suggest that the
prevalence of PanNETs may be higher than we expect, with prevalence rates of 3%
to 10%.79
RELEVANT ANATOMY/PATHOPHYSIOLOGY

Traditionally, PanNETs have been thought to arise from the islets of Langerhans that
perform the endocrine function of the pancreas. More recent investigation, however,
has demonstrated that these neoplasms originate from pluripotent cells in the
pancreatic ductal/acinar system.10 All PanNETs express neuroendocrine markers,
such as synaptophysin, neuron-specific enolase, and chromogranin A (CgA) (present
in 88%100% of patients with PanNETs). A multitude of cellular and molecular alterations have been implicated in the pathogenesis of PanNETs, involving at least
14 different types of cells and genetic alterations in the MEN-1 gene, the p16/MTS1
tumor-suppressor gene, the DPC4/Smad 4 gene, amplification of the Her-2/neu
proto-oncogene, and alterations in transcription factors Hox C6, growth factors,
and their receptor expressions.11 Several of these genetic alterations have been
shown to correlate with tumor aggressiveness and may have prognostic significance.12 This molecular heterogeneity translates to heterogeneity in the clinical presentation, including both the multiple syndromes of overproduction and
hypersecretion of hormones that have traditionally characterized these tumors as
well as hormonally silent tumors. Thus, PanNETs are often classified as functional
or nonfunctional based on the presence or absence of a particular clinical syndrome
associated with hormone hypersecretion. According to the SEER database, from 1973
to 2000, most PanNETs diagnosed were nonfunctional tumors (90.8%); the remaining
9% included malignant functional tumors, such as gastrinomas (4.2%), insulinomas
(2.5%), glucagonomas (1.6%), and VIPomas (0.9%).13,14 In addition to variability in
the production of pancreatic endocrine hormones, PanNETs exhibit a broad range
of growth rates, malignant potential, and overall prognosis. Although commonly
perceived to be indolent tumors because they have a far better prognosis than pancreatic adenocarcinoma, most patients with PanNETs (60%70%) present with metastatic disease.4,13,14 Even when they are resectable, many patients ultimately succumb to
the disease. Following surgical resection of PanNETs, the 5-year survival for PanNETs
other than insulinomas is roughly 65%, with a 10-year survival of 45%.14
In 2000, the WHO introduced a classification system based on clinical and histopathologic features that divides PanNETs into well-differentiated endocrine tumors
with either benign or uncertain behavior, well-differentiated endocrine carcinomas,
or poorly differentiated endocrine carcinomas.15 More recent classification systems
have acknowledged the increasing importance of a proliferative index, specifically
expression of the nuclear antigen Ki-67, and evidence of its prognostic value for
PanNET.1517 In 2010, the WHO revised the classification of PanNETs to reflect
a proliferation-based grading system in conjunction with the traditional histopathologic diagnostic criteria (Table 1). They delineated a 3-tier grading system of
PanNETs designating tumors as well-differentiated NETs versus poorly differentiated

Nonfunctional Pancreatic Neuroendocrine Tumors

Table 1
WHO classification of PanNETs
Grade

Ki-67 Index (%)

Mitotic Count/10 HPF

G1

2

<2

G2

320

220

G3

>20

>20

TNM

Size (cm)

Muscularis Propria Invasion

T1a

<1

T1b

12

T2

>2

In the World Health Organization (WHO) 2010, the higher grade is assumed if the Ki-67 index and
mitotic count differ; in the WHO 2010 TNM, the tumor is classified as T2 if it is larger than 2 cm in
diameter or if it invades the muscularis propria. T3 and T4 tumors are locally aggressive tumors
(data not shown in the table).
Abbreviation: HPF, high-power field.
Data from Bosman F, Carneiro F, Hruban R, editors. WHO classification of tumors of the digestive
system. Lyon (France): IARC Press; 2010.

neuroendocrine carcinomas. The well-differentiated NETs were further divided into

grade 1 (Ki-67 <2%) and grade 2 (Ki-67 of 2%20%). The poorly differentiated tumors
are considered grade 3 (Ki-67 >20). Mitotic rate or Ki-67 should be assessed on all
PanNETs. When both mitotic rate and Ki-67 are obtained, the higher grade is
assigned. If the biopsy specimen is inadequate, a repeat biopsy is recommended.18
The European Neuroendocrine Tumor Society (ENETS) and the American Joint
Committee on Cancer (AJCC) describe alternative classification systems for PanNETs. The ENETS classification19 for PanNETs combines a staging TNM classification including the tumor diameter along with a grading system based on the mitotic
rate and Ki-67.20 The AJCCs TNM classification is based on a staging system for
exocrine pancreatic adenocarcinomas, differentiating tumors based on the extent of
disease rather than the tumor grade to determine tumor resectability.20 Although
both systems emphasize different tumor characteristics, both classification systems
have been demonstrated to be prognostic for relapse-free survival.20 It is important
to note that histopathology is not always predictive of malignancy, and the only true
measures of whether a PanNET is benign or malignant include evidence of local invasion, metastases, and/or recurrent disease.
CLINICAL PRESENTATION

Most PanNETs are sporadic and tend to affect older individuals. Men have a slightly
increased risk of developing PanNETs than women (55.2% vs 44.8%), and there
is a Caucasian predominance in the United States (84.1% Caucasian vs 15.9% other
background).13 Functional tumors present with symptoms that result from the
specific hormone being elaborated. The most common functional PanNETs are insulinomas composing 30% to 45% of functioning PanNETs2,21 and gastrinomas
composing 16% to 30%.21 Glucagonoma, VIPomas, and somatostatinomas are
rarer PanNETs, and other rare functional PanNETs also exist.22 The presentation of
these tumors is summarized in Table 2 but is not discussed in further detail in this
article.
Patients with nonfunctional tumors typically present with symptoms related to local
mass effect or metastatic disease, indicating a more advanced stage of disease.9

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Table 2
Summary of functional NETs
Tumor Type

Numbera

Secretory Hormone

Clinical Features

Laboratory Tests

Symptomatic Treatment

Insulinoma

40%60%

Insulin

Hypoglycemia; symptoms of
catecholamine excess; 90%
benign

Insulin level, C-reactive

protein; 72-h inpatient
fasting with monitoring of
glucose and insulin levels

Dietary modifications;
octreotide; diazoxide

Gastrinoma

20%50%

Gastrin

Peptic ulcer disease; GERD;

secretory diarrhea; most
common PanNET in MEN-1;
60%90% malignant

Fasting serum gastrin; gastric

pH analysis, gastrin
provocation testing (calcium
or secretin challenge)

Proton pump inhibitor;

octreotide

Glucagonoma

Rare

Glucagon

Glucose intolerance; migratory

necrolytic erythema; weight
loss; anemia; 90% malignant

Serum glucagon

Octreotide; insulin; zinc

supplement (rash); TPN
(malnutrition)

Somatostatinoma

Rare

Somatostatin

Diabetes; gallstones; secretory

diarrhea

Clinical and pathologic

diagnoses; increased
somatostatinlike
immunoreactivity in resected
tumor

Octreotide

VIPoma

Rare

Vasoactive intestinal
peptide

Choleralike, secretory
diarrhea; hypokalemia;
hypochlorhydria

Serum VIP

Octreotide

Abbreviations: GERD, gastroesophageal reflux disease; MEN-1, multiple endocrine neoplasia type 1; TPN, total parenteral nutrition; VIP, vasoactive intestinal
polypeptide.
a
Percentage among PanNETs.

Nonfunctional Pancreatic Neuroendocrine Tumors

Nonfunctioning tumors either do not produce any hormone, produce very small
amounts of hormones that are insufficient to produce symptoms, or produce hormones that do not generate specific symptoms (pancreatic polypeptide, human chorionic gonadotropin subunits, calcitonin, or neurotensin).23,24 Most nonfunctional
tumors occur in the head of the pancreas and often produce symptoms of mass effect
that mimic those of pancreatic adenocarcinoma, including jaundice, abdominal
pain, weight loss, abdominal mass, nausea and vomiting, backache, and pancreatitis.22,25,26 As previously mentioned, the number of pancreatic tumors discovered
incidentally before any onset of symptoms is dramatically increasing because of the
widespread use of abdominal imaging.6,9,23 Bruzoni and colleagues27 found that
19% of these pancreatic incidentalomas were NETs on the final pathology.
Although most PanNETs occur sporadically, nearly 10% are associated with predisposing genetic syndromes. These hereditary syndromes include multiple endocrine
neoplasia type 1 (MEN-1 syndrome), von Hippel-Lindau disease (VHL), von Recklinghausen disease or neurofibromatosis type 1 (NF-1), and tuberous sclerosis complex
(TSC).2,9,14,21 These patients are generally diagnosed at a younger age, have multiple
synchronous lesions throughout the pancreas, and have a family history of endocrine
disorders or their associated cancers.9,21 The most recognized of these hereditary
syndromes is MEN-1.2,9,14,21 Most patients with MEN-1 (80%100%) develop
nonfunctioning PanNETs, 50% to 60% develop gastrinomas, 20% insulinomas, and
3% to 5% VIPomas or glucagonomas.2,9,14,21 Nonfunctional PanNETs, cystic pancreatic lesions, and mixed serous-NETs can be seen in 20% of patients with VHL.2,14,21 In
contrast to MEN-1 and VHL, PanNETs are relatively uncommon in patients with NF-1
and TSC (<10%).2,14,21
The evaluation of patients with PanNETs should include a comprehensive history
assessing for signs or symptoms of tumor mass effect, metastatic disease, or specific
functioning tumors. Eliciting a family history or genetic testing can determine whether
the tumor is sporadic or associated with a genetic syndrome and can have a significant impact on preoperative planning. For example, patients with MEN-1 are more
likely to have multiple tumors throughout the pancreas necessitating altered surgical
planning.
DIAGNOSIS

When a tumor of neuroendocrine origin is suspected, a complete biochemical evaluation looking for the most commonly secreted pancreatic hormones should be performed to determine functionality. Levels of NET markers can be very helpful for
diagnosis and determining the prognosis of nonfunctional PanNETs.2,11 Serum chromogranin A, a 49-kd protein contained in the neurosecretory vesicles of the NET cells,
is the most widely used as it reflects tumor burden. It is most helpful for welldifferentiated NETs. Elevated plasma chromogranin A levels have been associated
with a poor overall prognosis, and early decreases may be associated with favorable
treatment outcomes. It can be helpful in screening for persistent, recurrent, or metastatic disease11; the recent North American Neuroendocrine Tumor Societys management guidelines recommend following chromogranin A levels in patients with
advanced disease and in patients who have elevated CgA levels at diagnosis and to
consider following levels in those who have undergone resection.18 Elevated CgA
levels can also be caused by renal or liver failure and the use of proton-pump
inhibitors.
The PP cells of the islets of Langerhans secrete pancreatic polypeptide. It is found to
be elevated in 63% of PanNETs28 but has not been widely used because of its low

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sensitivity. However, high pancreatic polypeptide levels at baseline may be useful in

identifying false-negative CgA determinations in the diagnosis of PanNETs and has
a high specificity for follow-up in predicting controlled disease (84%).29 When there
is concordance of CgA and PP levels in follow-up, the ability to predict an increase
in tumor burden is increased (from 51%54% independently to 81% together).29
The diagnostic accuracy of CgA and PP may be lower in the MEN-1 patient
population.30
Pancreastatin, a posttranslational fragment of CgA, has shown diagnostic value in
monitoring carcinoid tumors. Its levels are not influenced by decreased acid production and, thus, may lead to fewer false-positive determinations. Recent studies have
shown some promise in using pancreastatin as a diagnostic and prognostic tumor
marker for NETs.31
Neuron-specific enolase (NSE) is another tumor marker that is found to be elevated
in 50% of NETs, most commonly in pulmonary NETs. High levels of NSE have been
associated with poorly differentiated NETs.32 Synaptophysin, glucagon, progastrinreleasing peptide, and cytokeratin fragments have all been evaluated as potential
tumor markers but have low sensitivity for detecting NETs.33
Screening for MEN-1 with measurement of parathyroid hormone and calcium levels
is also recommended given the high prevalence of PanNETs (80%100%) in this
patient population.2,23
DIAGNOSTIC PROCEDURES

The diagnosis of PanNETs centers on biopsy and staging of the disease. Crosssectional imaging studies with either a multiphasic CT scan or magnetic resonance imaging (MRI) dedicated to the evaluation of the pancreas play a key role.
CT

 It is recommended for the initial evaluation of PanNETs.

 PanNETs are well circumscribed, hypervascular lesions (Fig. 1).
 It has a sensitivity of 80% to 100% (decreased in tumors smaller than 2 cm, but
most symptomatic nonfunctioning tumors are >3 cm).

Fig. 1. PanNETs appear as well-circumscribed, hypervascular lesions on CT imaging. CT has a

high sensitivity for detecting PanNETs greater than 2 cm in size and offers excellent
anatomic and spatial detail. Arrow points to neuroendocrine tumor.

Nonfunctional Pancreatic Neuroendocrine Tumors

 The sensitivity of contrast-enhanced CT approaches 100% (imaging study of

choice).
 Dual-phase (arterial and portal) imaging detects pancreatic neoplasms and delineates local vascular anatomy.
 Oral contrast allows optimum visualization of the duodenum, improving the
detection of duodenal gastrinomas.
MRI

 PanNETs are typically characterized by low signal intensity on T1-weighted

images and high signal intensity on T2-weighted images. (Tumors <1 cm are
not detected by MRI with gadolinium; 50% of tumors between 1 and 2 cm are
identified.)34
 Larger tumors can be visualized without contrast.
 It has a greater sensitivity for liver metastases than CT or somatostatin receptor
scintingraphy.35
Endoscopic Ultrasonography

 Able to detect small tumors as small as 2 to 3 mm in diameter

 Sensitivity of 79% to 82%, specificity of 95%36,37
 Enables histologic analysis with endoscopic ultrasonography (EUS)-guided fineneedle aspiration38
 Useful in MEN-1 detecting 55% to 100% of nonfunctional PanNETs in asymptomatic patients39
 Operator dependent
Somatostatin Receptor Scintigraphy (Indium In Pentetreotide [Octreoscan])

 Uses indium- 111-labeled somatostatin analogue resulting in high-resolution imaging of the pancreas
 Effective for visualizing gastrinomas (100%), glucagonomas, and nonfunctioning
pancreatic tumors
 Not sensitive for detection of insulinomas and poorly differentiated NETs
 Additional advantage of whole-body scanning allowing for detection of metastatic disease outside of the abdomen (Fig. 2)
 Provides functional information on level of somatostatin receptor expression,
which may be used to guide somatostatin-based therapies in patients with
advanced disease
 Does not provide information on tumor size or surgical resectability
 Accuracy improved with fusion of somatostatin analogues to positron emission
tomography isotopes in single-photon emission CT; allows differentiation between areas of pathologic and physiologic uptake in the abdomen
Fig. 3 provides a simple algorithm summarizing the diagnostic tests for PanNETs.
Other diagnostic procedures, including visceral arteriography and selective intraarterial stimulation, are used to localize occult functional tumors.
SURGICAL MANAGEMENT

Surgical resection is the only curative therapy for functional and nonfunctional
PanNETs and is the cornerstone of the treatment of patients with PanNETs without evidence of metastatic disease or significant comorbidities. There is a significant survival
benefit in patients with localized, regional, and metastatic disease who undergo resection (average overall survival 114 months vs 35 months) when compared with those

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Fig. 2. Somatostatin receptor scintigraphy (indium In 111 pentetreotide [Octreoscan]) allows whole-body imaging and is sensitive for detecting metastatic disease, especially
outside of the abdomen. It also allows assessment of somatostatin receptor expression levels
that can be used to guide systemic therapy.

who did not undergo surgery.40 Thus, surgical therapy should be considered if most
(approximately 90%) of the gross disease can be resected safely. The primary exception to this rule is PanNETs associated with MEN-1 and Zollinger-Ellison syndrome
whereby tumors tend to be multiple and nonfunctional and may warrant close surveillance and/or symptom management.
Given the variable biology and behavior of PanNETs, deciding on the appropriate
surgical therapy requires taking into account a myriad of factors, including risk of
malignancy, presence/absence of metastases, as well as the patients overall health
and wishes. Fig. 4 summarizes an algorithm that provides guidance on the surgical
treatment of patients with solitary PanNETs. In general, nonfunctional PanNETs
should undergo resection. However, evidence is emerging that with more accurate
pathologic analysis of biopsy material, there are situations when small lesions can
be observed. Most nonfunctional PanNETs are malignant as manifested by local invasion, lymph node involvement, and/or liver metastases. Patients without evidence
of metastatic disease should be treated with formal resection and lymphadenectomy. Patients with low-grade metastatic disease should be treated with surgical
resection (including resection of metastatic sites) in conjunction with adjuvant therapies, such as ablation, embolization, hormonal therapy, and chemotherapy. Patients
with high-grade metastatic disease should receive medical therapy, often including
cytotoxic chemotherapy.
All nonfunctional PanNETs greater than 3 cm should be resected if possible. Controversy exists as to whether enucleation is sufficient resection for nonfunctional
PanNETs smaller than 3 cm. In a retrospective review of 318 patients with sporadic,
nonfunctional, nonsyndromic PanNETs resected at a single institution, 9% to 37%
of tumors less than 3 cm in size were associated with lymph node metastases.
They also found on multivariate analysis that the presence of positive lymph nodes
conferred a poorer survival.41 Therefore, formal resection is preferred over enucleation

Nonfunctional Pancreatic Neuroendocrine Tumors

Fig. 3. Algorithm for diagnostic tests.

for nonfunctional PanNETs smaller than 3 cm in size. However, enucleation may be

appropriate in elderly patients or those with significant comorbidities, a tumor with a
low proliferative index, and patients who do not wish to have a formal resection.42
Central pancreatectomy is another parenchyma-sparing procedure that can be
considered for small benign lesions.43
For even smaller tumors less than 2 cm, surgical resection may not necessarily be
mandated. The ENETS guidelines state no data exist with respect to a positive effect
of surgery on overall survival in small (<2 cm), possibly benign or intermediate-risk
pancreatic endocrine tumors and advocate careful balancing of surgical risk before
proceeding to resection over observation.44 Lee and colleagues45 described a cohort
of 67 patients with small (median size 1 cm), incidentally found nonfunctional PanNETs
who were observed for a median of 45 months. There were no cases of disease progression over this observation period. Therefore, for small tumors less than 2 cm
with a low proliferative index (Ki-67), observation may be an appropriate option.
Table 3 summarizes the surgical options for management of PanNETs.
There have been descriptions and small series of minimally invasive approaches
to most of the types of pancreatic resections. These approaches include laparoscopic and robotic techniques for both traditional, formal resections like pancreaticoduodenectomy to parenchyma-sparing operations like enucleations and central

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Fig. 4. Decision tree for surgical resection of PanNET. PD, pancreatic duct. * Refer to text for
discussion of enucleation versus formal resection.

pancreatectomies. The most commonly performed minimally invasive pancreatic

operations are laparoscopic enucleations and laparoscopic distal pancreatectomy.
Gagner and colleagues46 first described their approach to the laparoscopic distal
pancreatectomy with spleen preservation for insulinoma in 1996. It has become
the gold standard for small, benign lesions or low-grade malignancies. In 2012, a
meta-analysis showed that laparoscopic distal pancreatectomy resulted in
decreased morbidity (39.3% vs 44.2%), with decreased estimated blood loss by
approximately 350 mL and a decreased length of hospital stay by 4 days.47 They
found no difference in operative time, margin positivity, incidence of postoperative
pancreatic fistula, and mortality.
Although laparoscopic pancreaticoduodenectomy was described before laparoscopic distal pancreatectomy in 1994,48 the technique has been slow to gain popularity because of the complex technique and long operative times. However, a
recent meta-analysis showed statistically significant differences with respect to less
blood loss, lower transfusion rates, lower wound infection rates, lower morbidity rates,
and shorter hospital stays. The laparoscopic approach is significantly longer
compared with the open approach for pancreaticoduodenectomy.49 There was no
significant difference in oncological outcomes between laparoscopic pancreatectomy
and the open technique.49 Although there is often a learning curve involved, laparoscopic operations can be performed safely and offer a good alternative to formal
open operations in the appropriate patients.
Robotic surgery has quickly evolved over the last decade, and several case series
describing robotic approaches to distal pancreatectomy and pancreaticoduodenectomy have been published. Cirocchi and colleagues50,51 reviewed these studies and
concluded that although the operative times were longer for robotic distal pancreatectomy and pancreaticoduodenectomy, the robotic technique is feasible with similar
morbidity and mortality to the laparoscopic and open techniques and is associated
with a decreased length of hospital stay with distal pancreatectomies.50 They

Table 3
Summary of operative management options for PaNETs
Procedure

Approach

Indications

Contraindications

Outcomes

Pancreaticoduodenectomy

Most commonly open

Laparoscopic approach
gaining popularity
Robotic approach being
investigated

Large tumors of the pancreatic

head, uncinate, or neck

Involvement of the superior

mesenteric artery
Exclusion based on portal vein
involvement may vary by
institution

Significant survival benefit in

patients who undergo
resection9

Distal pancreatectomy

Open
Laparoscopic

Large tumors of the pancreatic

body or tail

Splenic preservation
contraindicated for patients
with suspected malignancy

Laparoscopic approach affords

better postoperative pain,
shorter hospital stay, shorter
recovery, and better
cosmesis40

Traditional resections

Enucleation

Open
Laparoscopic

Tumors 3 cm in size

Large tumors
Nodal or metastatic disease
Lesions in close proximity to
the pancreatic duct

Similar morbidity and 5-y

survival as traditional
resections53
Increased rate of pancreatic
fistulas but less severe
Decreased blood loss,
operative time, and length
of hospital stay

Central pancreatectomy

Open
Laparoscopic

Small, benign, or low-grade

tumors of the neck or
proximal body of the
pancreas

High-grade and/or advanced

tumors

Better preservation of
pancreas function with
similar morbidity and
mortality43

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Parenchyma-sparing resections

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concluded that randomized trials were needed to compare oncologic outcomes and
the cost-effectiveness of these procedures.
MANAGEMENT OF HEPATIC METASTASES

The liver is the predominant site of extranodal metastatic disease in PanNETs and is
the predominant cause of mortality in many patients. Resection of hepatic metastases
has been shown to improve outcomes in more than 90% of cases.11,5254 Survival
rates of approximately 60% are reported at 5 years after hepatic metastasectomy
compared with 30% in patients with untreated liver metastases,54,55 with a median
survival of 24 to 128 months. In patients without (or mild nonclinically significant)
extrahepatic disease, resection should be considered for treatment. Asymptomatic
patients who have resectable disease should also be considered for surgical debulking. Table 4 summarizes the interventional treatment options for hepatic metastases
in patients who are not candidates for surgical resection. In general, the use of these
treatments either alone or in conjunction with surgical resection is recommended for
locoregional control and symptom relief.5658 Liver transplantation is a viable option
for symptomatic, well-differentiated gastrointestinal NETs when standard surgical
resection is not an option or for disease that has not responded to other treatment options. The 5-year survival rate is 45%.59 However, a primary PanNET was found to be a
negative prognostic factor60; therefore, liver transplantation is not recommended in
the treatment of NETs arising from the pancreas.
SYSTEMIC THERAPY

Patients with high-grade metastatic disease not amenable to surgical resection or

liver-directed therapies can be treated with multiple medical therapeutic approaches.
The goal of treatment is to improve quality of life and to extend progression-free survival as well as overall survival. Medical treatment can control the associated symptoms and signs of the specific tumors and shrink tumor mass.
Somatostatin Analogues

Octreotide is the prototypical somatostatin analogue used to treat patients with

advanced PanNETs. Nearly 80% of NETs express somatostatin receptors as evidenced by radiotracer uptake on Octreoscans, providing an effective means of
delivering cytotoxic treatments to neoplastic cells.61 Radiolabeled somatostatin analogues bind to the somatostatin receptor, and a fraction of the ligand-receptor complex is internalized, delivering targeted radiotherapy to PanNETs.62 The most
frequently used radionuclides for therapy in PanNETs are indium, yttrium, and lutetium, which differ from one another in terms of emitted particles, particle energy,
and tissue penetration.63 Overall, tumor response rates have been reported between
30% and 50%; stable disease following treatment has been reported in up to
70%.64,65 In the PROMID study, the use of octreotide-LAR (octreotide acetate longacting injectable solution) increased the time to progression (14.3 months) as
compared with placebo (6 months).66 Stable disease was achieved in 66.7% and
37.2% of patients with octreotide-LAR and placebo, respectively. It was found to
be effective in both functioning and nonfunctioning tumors. The duration of the therapy
response is reported to be greater than 30 months; when kidney protective agents are
used, the side effects of this therapy are few and mild.65 Ongoing clinical trials are
evaluating the efficacy of novel somatostatin analogues (SOM230 or pasireotide)
that have 30 to 40 times higher binding affinity to somatostatin receptors than octreotide and lanreotide.67

Table 4
Summary of interventional liver-directed therapies for metastatic PaNETs
Indications

Contraindications

Approach

Outcomes

Hepatic artery embolization

Palliation of patients who are

not candidates for surgical
resection
Metastasis limited to the liver

Prior
pancreaticoduodenectomy
Significant hepatic
insufficiency
Portal vein thrombosis
Poor performance status

Bland embolization: infusion

of absorbable gelatin
sponge (Gelfoam) powder
Chemoembolization (TACE):
infusion of cytotoxic drugs
(doxorubicin, cisplatin, and
streptozocin) or use of
drug-eluting beads
Radioembolization: use of
radioactive isotopes (eg,
yttrium-90)

Response rates generally

exceed 50%5860

Radiofrequency ablation,
microwave ablation, and
cryoablation

Patients with <10 lesions,

each lesion <4 cm in size
Small tumors deep in hepatic
parenchyma

Large tumors

Used alone or in combination

with surgical resection
Percutaneous or laparoscopic
approach

Morbidity benefit when

compared with hepatic
arterial embolization
Recurrences common, but
multiple treatments may
be given with good
tolerance

Infusional chemotherapy

Uncommon technique
Used in conjunction with
radiotherapy

Diffuse disease

Percutaneous infusion of 5FU or melphalan with

extraction of the drug from
hepatic veins
Multiple treatments possible

Good locoregional control

with tumor response seen
in 80% of patients when
combined with
radiotherapy58

Abbreviations: TACE, trans-arterial chemoembolization; 5-FU, 5-fluorouracil.

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Treatment

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Peptide receptor radionucleotide therapy is a newer treatment option that couples

cytotoxic drugs to somatostatin analogues to target PanNETs. Initially octreotide was
used, but this has been largely replaced by yttrium-90 or lutetium-177 coupled
analogues. This treatment has been shown to be effective for both symptom relief
and tumor remission. Adverse effects are typically mild and limited primarily to toxicity
to the bone marrow and kidneys.68
Cytotoxic Chemotherapy

Historically, well-differentiated PanNETs have been resistant to standard chemotherapy, with reported response rates varying from 8% to 45%.69 Because of the
limited efficacy of these agents, they were often started when patients demonstrated
progressive disease despite somatostatin analogues. More recently, a randomized
trial comparing the combination of streptozocin with doxorubicin versus streptozocin
with fluorouracil demonstrated a mortality benefit as well as radiological and biochemical regression of disease in 69% of patients.70 Therapy with streptozocin is limited by
its toxicity and cumbersome administration schedule. Oral temozolomide (an alkylating agent) is better tolerated and has been shown to have comparable efficacy.70 An
18-month median progression-free survival in patients with metastatic PanNETs was
demonstrated in patients who received temozolomide and capecitabine.62 Cytotoxic
therapies should be considered in the palliation of patients with advanced PanNETs
and symptoms related to tumor bulk.
Targeted Therapy

NETs have been shown to express a multitude of growth factors and their corresponding receptors leading to the development of targeted therapeutic agents. Recent
phase III studies have shown tremendous promise for 2 drugs designed for targeted
therapy in the treatment of PanNETs, everolimus and sunitinib. Both drugs are recommended for patients with progressive metastatic PanNETs.
Everolimus

mTOR (mammalian target of rapamycin) is a serine/threonine kinase involved in the

regulation of cell growth and death through apoptosis. It is also capable of impacting
multiple downstream pathways, including vascular endothelial growth factor (VEG-F)
and other growth factors. There is a relationship between the TSC and the phosphatase and tensin homolog (PTEN), NF-1, and VHL genes that contribute to the development of neuroendocrine tumors. Downregulation of TSC2 and PTEN have been shown
to be a poor prognostic factor in PanNETs, supporting an important role for the PI3K/
Akt/mTOR pathway and its inhibition in the treatment of PanNETs.69,71,72 Everolimus
(RAD001), an oral mTOR inhibitor, has been shown to have antitumor activity in many
solid tumors, including PanNETs. The RAD001 in Advanced Neuroendocrine Tumors3 (RADIANT-3) study by Yao and colleagues73 is a randomized phase 3 study evaluating the efficacy of everolimus in advanced PanNETs. In this international multisite
study, 410 patients with low- or intermediate-grade, progressive, advanced PanNETs
were randomized to receive everolimus, 10 mg oral daily, or placebo. The response
rate was 5% in the everolimus arm compared with 2% in the placebo arm, with a median progression-free survival of 11.0 months with everolimus compared with
4.6 months with placebo (hazard ratio, 0.35; 95% confidence interval, 0.270.45;
P<.001). The median overall survival has not been reached. The Food and Drug
Administration (FDA) has approved everolimus for advanced PanNETs. Adverse
events associated with everolimus are rare and most commonly include stomatitis,
rash, diarrhea, fatigue, infections, and pneumonitis.

Nonfunctional Pancreatic Neuroendocrine Tumors

Sunitinib

PanNETs express an abundance of VEG-F and platelet-derived growth factor (PDGF)

receptors. Three tyrosine kinase inhibitors have shown activity against VEG-F receptor: pazopanib, sorafenib, and sunitinib. Sunitinib is an oral, small-molecule, multi-targeted tyrosine kinase inhibitor with activity against VEG-F and PDGF. A phase II trial
demonstrated a response rate of 17% with a stable disease rate of 68%.74 In
a multinational randomized controlled trial of 171 patients with advanced, welldifferentiated, and progressive pancreatic neuroendocrine carcinomas, patients
were randomized to receive sunitinib, 37.5 mg orally daily, or placebo. Sunitinib
increased progression-free survival (11.4 months) versus placebo (5.5 months,
P<.0001).75 This study was terminated early because of more serious adverse events
and deaths in the placebo group (25%) compared with the group receiving sunitinib;
thus, the benefit in overall survival could not be determined. It can also be safely combined with somatostatin analogues without affecting the quality of life. Adverse events
associated with sunitinib include diarrhea, nausea, asthenia, vomiting, fatigue, and hypothyroidism. The FDA and European Medicines Agency have approved sunitinib for
the treatment of unresectable or metastatic, well-differentiated PanNETs with disease
progression in adults.
Bevacizumab

Bevacizumab is a humanized monoclonal antibody that inhibits VEG-F and has

recently been tested in combination with capecitabine and oxaliplatin for patients
with advanced neuroendocrine tumors.76 In patients with PanNETs, 30% exhibited
partial responses with a median progression-free survival of 13.7 months. Prospective, randomized phase III studies combining bevacizumab with octreotide, temozolomide, CAPOX (oxaliplatin and capecitabine), FOLFOX (oxaliplatin and fluorouracil),
and everolimus are still ongoing.77,78
SUMMARY

PanNETs are a heterogeneous group of tumors that pose a significant challenge

because of the heterogeneous clinical presentations and varying degree of aggressiveness. The incidence of PanNETs is increasing, in part, because of the increased
use of cross-sectional imaging and increased incidence of pancreatic incidentalomas.
Most PanNETs are nonfunctional tumors, and most are malignant in nature. Surgery
remains the only curative modality for PanNETs; resection of the primary tumor in
localized, regional, and even metastatic disease can improve patient survival. Selecting an operative approach for PanNETs is a complex decision that must consider a
myriad of factors, including functional status, benign or malignant nature, involvement
with contiguous structures, presence of metastatic disease, proliferative index, and
whether the tumor is sporadic or associated with a genetic syndrome. Indications
for surgery in patients with nonfunctional PanNETs include local compressive symptoms caused by mass effect and prevention of malignant transformation or dissemination. In general, nonfunctional PanNETs, even those smaller than 3 cm, are best
treated with formal resection and appropriate lymphadenectomy because a significant
percentage of even small nonfunctional PanNETs will have lymph node metastases.
However, in certain clinical scenarios (eg, low Ki-67, patient with significant comorbidities, patient who does not want an extensive resection, and so forth), nonfunctional
PanNETs that are 3 cm or less in size that do not impinge on the common bile or
pancreatic ducts can be enucleated. There is evidence to suggest observation is
appropriate for selected patients with tumors smaller than 2 cm and a low proliferation
index. PanNETs greater than 3 cm should be resected with an appropriate oncologic

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operation based on the location within the pancreas. For lesions located in the head,
uncinate, or neck of the pancreas, pancreaticoduodenectomy can be performed. For
lesions located in the body or tail of the pancreas, distal pancreatectomy can be performed. For lesions in the neck and proximal body, either an extended pancreaticoduodenectomy or extended distal pancreatectomy may be performed depending on
the specific anatomy. For select lesions in the neck and proximal body of the
pancreas, central pancreatectomy may be performed. Patients with evidence of metastatic hepatic disease should be considered for metastasectomy if possible. In those
patients who are not surgical candidates, early, aggressive treatment of unresectable
liver metastases using interventional techniques may improve symptom relief and
quality of life and should be considered for palliation of disease. For patients with
advanced, metastatic disease not amenable to surgical resection, somatostatin analogues and targeted therapies offer promising therapeutic alternatives for decreasing
morbidity and increasing progression-free survival.
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